Point Mutations in the Human Vitamin D Receptor Gene Associated with Hypocalcemic Rickets
Hypocalcemic vitamin D--resistant rickets is a human genetic disease resulting from target organ resistance to the action of 1,25-dihydroxyvitamin D$_{3}$. Two families with affected children homozygous for this autosomal recessive disorder were studied for abnormalities in the intracellular vitamin...
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Published in | Science (American Association for the Advancement of Science) Vol. 242; no. 4886; pp. 1702 - 1705 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
The American Association for the Advancement of Science
23.12.1988
American Association for the Advancement of Science |
Subjects | |
Online Access | Get full text |
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Summary: | Hypocalcemic vitamin D--resistant rickets is a human genetic disease resulting from target organ resistance to the action of 1,25-dihydroxyvitamin D$_{3}$. Two families with affected children homozygous for this autosomal recessive disorder were studied for abnormalities in the intracellular vitamin D receptor (VDR) and its gene. Although the receptor displays normal binding of 1,25-dihydroxyvitamin D$_{3}$ hormone, VDR from affected family members has a decreased affinity for DNA. Genomic DNA isolated from these families was subjected to oligonucleotide-primed DNA amplification, and each of the nine exons encoding the receptor protein was sequenced for a genetic mutation. In each family, a different single nucleotide mutation was found in the DNA binding domain of the protein; one family near the tip of the first zinc finger (Gly$\rightarrow $Asp) and one at the tip of the second zinc finger (Arg$\rightarrow $Gly). The mutant residues were created in vitro by oligonucleotide directed point mutagenesis of wildtype VDR complementary DNA and this cDNA was transfected into COS-1 cells. The produced protein is biochemically indistinguishable from the receptor isolated from patients. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0036-8075 1095-9203 |
DOI: | 10.1126/science.2849209 |